Description: (Taken directly from the application) Polycystic kidney disease (PKD) is a multigene disorder characterized by the growth of fluid-filled cysts, mainly in the kidney. Mutations in at least three genes, PKD1, PKD2 and PKD3, may give rise to the autosomal dominant form of PKD (ADPKD). Evidence suggests that the etiology of cyst initiation associated with PKD1 mutations results from two separate gene inactivation events. The first is an inherited mutation in one PKD1 allele; the second mutation arises in the normal allele during kidney development or maturation. We will test this "second hit" hypothesis as a mechanism for the onset of polycystic kidney disease by producing mice containing both a primary mutation in Pkd1 and a conditional second-hit mutation that can be induced somatically in the other murine Pkd1 allele. These mice will be analyzed for phenotypes associated with ADPKD. Additionally, the combination of mutations will test the Pkd1 missense mutation (Project 3) in a more physiologically relevant model. Finally, the long-range goal of this project is to generate an animal model in which the development of renal, hepatic and other pathophysiology associated with polycystic kidney disease can be analyzed and understood and in which modes of treatment can be tested.